14-3-3 Proteins Reduce Cell-to-Cell Transfer and Propagation of Pathogenic α-Synuclein

alpha-Synuclein (alpha syn) is the key protein that forms neuronal aggregates in the neurodegenerative disorders Parkinson's disease (PD) and dementia with Lewy bodies. Recent evidence points to the prion-like spread of alpha syn from one brain region to another. Propagation of alpha syn is likely dependent on release, uptake, and misfolding. Under normal circumstances, this highly expressed brain protein functions normally without promoting pathology, yet the underlying endogenous mechanisms that prevent alpha syn spread are not understood. 14-3-3 proteins are highly expressed brain proteins that have chaperone function and regulate protein trafficking. In this study, we investigated the potential role of the 14-3-3 proteins in the regulation of alpha syn spread using two models of alpha syn spread. In a paracrine alpha syn model, 14-3-3 theta promoted release of alpha syn complexed with 14-3-3 theta. Despite higher amounts of released alpha syn, extracellular alpha syn showed reduced oligomerization and seeding capability, reduced internalization, and reduced toxicity in primary mixed-gender mouse neurons. 14-3-3 inhibition reduced the amount of alpha syn released, yet released alpha syn was more toxic and demonstrated increased oligomerization, seeding capability, and internalization. In the preformed fibril model, 14-3-3 theta reduced alpha syn aggregation and neuronal death, whereas 14-3-3 inhibition enhanced alpha syn aggregation and neuronal death in primary mouse neurons. 14-3-3s blocked alpha syn spread to distal chamber neurons not exposed directly to fibrils in multichamber, microfluidic devices. These findings point to 14-3-3s as a direct regulator of alpha syn propagation, and suggest that dysfunction of 14-3-3 function may promote alpha syn pathology in PD and related synucleinopathies.